Cholecystokinin (CCK) is an abundant neuropeptide that has been implicated as an endogenous regulator of appetite, an analgesic, and a remarkably potent antipsychotrophic agent. In receptor binding studies, the PI has found altered numbers of brain CCK receptors associated with obesity, developmental ontogeny, treatment with various psychoactive drugs, and human neurological disease, suggesting that these conditions may be accompanied by changes in the central nervous system (CNS) sensitivity to CCK. However, there is no bioassay for measuring CNS sensitivity to CCK. The proposed studies will identify specific neurochemical responses to CCK, thereby providing tools for the measurement of neurobiological responsiveness to CCK, as well as elucidating the basic mechanism of action of CCK in the brain. We plan to determine the effects of CCK on cyclic AMP and cyclic GMP production by tissue slices. Because the cyclic nucleotides commonly serve as "second messengers" in the action of hormones and neurotransmitters, these experiments will shed light on the mechanism of the CNS action of CCK. Othe work will test the effects of CCK on the influx and efflux of calcium and sodium in tissue slices and synaptosomes. As an excitatory neurotransmitter, CCK should enchance membrane permeability to these ions. The neurochemical potencies of several analogs of CCK also will be compared with the receptor binding potencies. These studies, therefore, will establish the biological relevance of CCK receptor binding measurements, provide a means of evaluating the CNS activity of analogs of CCK, enable testing for physiological and treatment effects on the CNS sensitivity to CCK, and thereby will facilitate future studies of the functions and practical uses of this important neuropeptide.